RESUMEN
BACKGROUND: The exact mechanism of aspirin-induced asthma is not clear. It has been postulated that precipitation of asthma attacks by aspirin is linked to inhibition of COX activity and massive release of cysteinyl leukotriene into the airway. Tacrolimus, a macrolide-derived immunosuppressant, is used for immunosuppression in organ transplantation and also for allergic diseases such as atopic dermatitis. OBJECTIVE: We evaluated the effects of tacrolimus in aspirin-induced asthma by using a double-blind, crossover study design. METHODS: Twelve patients with aspirin-induced asthma (male:female, 3:9; mean age +/- SD, 36.7 +/- 7.2 years) received either tacrolimus (0.1 mg/kg) or placebo 2 hours before the threshold dose of oral aspirin. RESULTS: In the placebo arm, oral aspirin significantly decreased FEV 1 concomitant with significant increases in sputum eosinophilic cationic protein and urinary leukotriene E(4) levels. Tacrolimus significantly inhibited bronchoconstriction and abrogated aspirin-induced increase in both sputum eosinophilic cationic protein and urinary leukotriene E(4) levels. CONCLUSION: The current study suggested that tacrolimus inhibited bronchoconstriction to a threshold dose of aspirin by inhibition of cysteinyl leukotriene excretion.
Asunto(s)
Aspirina/efectos adversos , Asma/inducido químicamente , Asma/prevención & control , Inmunosupresores/farmacología , Leucotrieno E4/orina , Tacrolimus/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/fisiología , Adulto , Broncoconstricción/efectos de los fármacos , Estudios Cruzados , Método Doble Ciego , Proteína Catiónica del Eosinófilo/análisis , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Approximately half of the Japanese asthmatics experience exacerbation of asthma after alcohol consumption. We previously reported that this phenomenon is probably caused by histamine release from mast cells by acetaldehyde stimulation. However, no reports have described the effects of acetaldehyde on human airway mast cells. The purpose of the present study was to demonstrate acetaldehyde-induced histamine release from human airway mast cells with subsequent airway smooth muscle contraction and to investigate the ensuing mechanisms. METHODS: Human tissue samples were prepared from the lungs resected from patients with lung cancer. The effect of acetaldehyde on airway muscle tone and the concentration of chemical mediators released in the organ bath were measured before and after acetaldehyde stimulation. Mast cells were prepared from lung parenchyma by the immunomagnetic method and then stimulated with acetaldehyde to determine the chemical mediators released. RESULTS: Acetaldehyde (>3 x 10(-4) M) increased airway muscle tone, which was associated with a significant increase in the release of histamine, but not thromboxane B2 or cysteinyl-leukotrienes. A histamine (H1 receptor) antagonist completely inhibited acetaldehyde-induced bronchial smooth muscle contraction. Acetaldehyde also induced a significant histamine release from human lung mast cells and degranulation of mast cells. CONCLUSIONS: The present results strongly suggest that acetaldehyde stimulates human airway mast cells to release histamine, which may be involved in bronchial smooth muscle contraction following alcohol consumption.
Asunto(s)
Acetaldehído/farmacología , Broncoconstricción/efectos de los fármacos , Liberación de Histamina/efectos de los fármacos , Pulmón/inmunología , Mastocitos/efectos de los fármacos , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Antagonistas de los Receptores Histamínicos/farmacología , Humanos , Leucotrienos/metabolismo , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Masculino , Mastocitos/metabolismo , Persona de Mediana Edad , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Técnicas de Cultivo de Órganos , Tromboxano B2/metabolismoRESUMEN
BACKGROUND: It has been demonstrated that both cysteinyl leukotrienes (cysLTs) and cytokines are involved in the pathophysiology of bronchial asthma. Nonetheless, the exact mechanism involved in the interaction between these 2 molecules has yet to be determined. OBJECTIVE: The aim of the present study was to determine the effects of cysLTs on allergic airway inflammation and allergen-specific cytokine production in a murine model of asthma. METHODS: Four groups of BALB/c mice (control mice, Dermatophagoides farinae allergen-sensitized mice, pranlukast cysLT receptor antagonist-treated allergen-sensitized mice, and dexamethasone-treated allergen-sensitized mice) were examined. RESULTS: Allergen-sensitized mice exhibited increased airway responsiveness and inflammation. Pranlukast-treated mice showed significant attenuation of these changes concomitant with reduction of T(H)2 cytokine and IFN-gamma production by isolated lung mononuclear cells (MNCs). A much stronger inhibition of all cytokines was noted in dexamethasone-treated mice. Pranlukast also significantly inhibited production of RANTES and activation of nuclear factor kappa B (NF-kappa B) in the isolated lung MNCs. Leukotriene D(4) stimulated isolated lung MNCs to produce RANTES but not any other cytokines and also activated NF-kappa B in these cells. CONCLUSIONS: Our results suggest that cysLTs activate NF-kappa B and induce RANTES production from isolated lung MNCs, which in turn might cause migration of eosinophils and activated T lymphocytes into the airway.
Asunto(s)
Asma/metabolismo , Quimiocina CCL5/biosíntesis , Cisteína/farmacología , Mediadores de Inflamación/farmacología , Leucotrienos/farmacología , FN-kappa B/metabolismo , Animales , Antígenos Dermatofagoides/inmunología , Asma/inmunología , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/fisiopatología , Bronquitis/inmunología , Bronquitis/patología , Cromonas/farmacología , Citocinas/biosíntesis , Femenino , Antagonistas de Leucotrieno/farmacología , Leucotrieno D4/farmacología , Pulmón/metabolismo , Pulmón/patología , Ratones , Ratones Endogámicos BALB C , Monocitos/efectos de los fármacos , Monocitos/metabolismo , FN-kappa B/antagonistas & inhibidores , Factor de Transcripción ReIARESUMEN
Stimulation by specific allergens induces inflammatory cytokine production from peripheral blood mononuclear cells (PBMCs) in patients with atopic asthma, but the mechanism remains unknown. PBMCs were collected from six patients with atopic asthma with an immunoglobulin E-radioallergosorbent test score to Dermatophagoides farinae of > or = 4 and six nonatopic healthy subjects (score = 0) using a dish adhesion method after density gradient centrifugation. CD23 expression in PBMCs was analyzed by the fluorescence-activated cell sorting method. PBMCs were incubated with D. farinae or lipopolysaccharide, and production of tumor necrosis factor (TNF) alpha into the supernatant was measured by enzyme-linked immunosorbent assay. After incubation, immunostaining nostaining of the PBMCs with anti-nuclear factor kappa B (NF-kappa B) antibody (anti-p65 antibody against p65 as the subunit of NF-kappa B) was performed, and NF-kappa B activation in extracted nuclear protein was examined by electrophoretic mobility shift assay. CD23 expression was significantly higher in PBMCs from patients with asthma than in the controls (p < 0.01). There was no significant difference in TNF-alpha production by lipopolysaccharide stimulation between the two groups, but D. farinae-specific TNF-alpha production was significantly higher in subjects with asthma than in the controls (p < 0.05). A significant translocation of NF-kappa B to nuclei by D. farinae stimulation was observed in cells from subjects with asthma (p < 0.01). Our results indicated that TNF-alpha production was induced by D. farinae in PBMCs of patients with atopic asthma by the activation of NF-kappa B via CD23. In patients with atopic asthma, CD23-mediated signals may cause proinflammatory cytokine production, which may lead to airway inflammation.
Asunto(s)
Alérgenos/efectos adversos , Alérgenos/metabolismo , Asma/inmunología , Hipersensibilidad Inmediata/metabolismo , Leucocitos Mononucleares/metabolismo , FN-kappa B/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Adulto , Formación de Anticuerpos/fisiología , Biomarcadores/análisis , Biotransformación/fisiología , Femenino , Citometría de Flujo , Humanos , Hipersensibilidad Inmediata/inmunología , Japón , Lipopolisacáridos/efectos adversos , Lipopolisacáridos/metabolismo , Masculino , Receptores de IgE/biosíntesis , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Corticosteroids form an important component of the treatment of acute asthma. Systemic anaphylactic reactions to intravenous corticosteroids have been reported, although their incidence is extremely rare. OBJECTIVES: To determine the clinical features and underlying mechanisms of anaphylactic reactions to intravenous corticosteroids in adult asthmatics. SUBJECTS AND METHODS: The clinical features of 7 adult asthmatics (4 males, 3 females, mean age 39.4 +/- 16.9 years), who had developed systemic anaphylactic reactions to intravenous administration of corticosteroids for the treatment of acute asthma, were studied retrospectively on the basis of their medical records. Skin tests using various injectable steroid preparations were performed in 3 cases to determine the mechanism of this reaction. RESULTS: Systemic anaphylactic reactions to intravenous administration of corticosteroids occurred in severe atopic asthmatics with previous exposure to parenteral corticosteroids, irrespective of age and gender. Aspirin-intolerant asthma was identified in only 3 subjects. In all cases, anaphylactic reactions were induced following intravenous administration of succinate-containing corticosteroid preparations, i.e. hydrocortisone and methylprednisolone. Administration of phosphate-containing corticosteroids, i.e. dexamethasone and betamethasone, was safe and resulted in a resolution of anaphylactic symptoms. Immunological examination with skin tests suggested that anaphylactic reactions were an IgE-mediated hypersensitivity. CONCLUSIONS: Intravenous injection of succinate-containing corticosteroids in high-risk asthmatics should be performed slowly by drip injection under continuous monitoring. Once anaphylactic reactions occur, it is important to stop the injection immediately and to use conventional medication for anaphylaxis.
Asunto(s)
Anafilaxia/inducido químicamente , Antiasmáticos/efectos adversos , Asma/tratamiento farmacológico , Glucocorticoides/efectos adversos , Adolescente , Adulto , Anciano , Antiasmáticos/administración & dosificación , Antiasmáticos/uso terapéutico , Femenino , Glucocorticoides/administración & dosificación , Glucocorticoides/uso terapéutico , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Steroid-induced adverse effects including suppression of humoral immunity should be considered in steroid-dependent severe asthma. Only a few studies have determined the exact steroid dose that could potentially suppress humoral immunity in asthmatics. METHODS: Randomly selected 100 adult asthmatics treated with inhaled beclomethasone dipropionate (BDP) were classified into three groups based on the dose of steroid to determine the serum IgG, IgA and IgM levels by radioimmunoassay. Relationships between serum immunoglobulin levels and the daily dose and duration of oral prednisolone (PSL) therapy were examined. RESULTS: None of the patients on inhaled corticosteroid alone had hypogammaglobulinemia. Patients on oral PSL at a dose >12.5 mg/day for at least 1 year had low serum IgG. There was no significant correlation between the duration of oral PSL therapy and serum IgG. CONCLUSIONS: Oral PSL can potentially suppress humoral immunity in severe asthma. In asthmatics, hypogammaglobulinemia could develop in those on a daily dose of PSL >12.5 mg, but is independent of the duration of such treatment. No suppression of humoral immunity was noted on inhaled corticosteroid therapy alone, either at low or high dose.
Asunto(s)
Agammaglobulinemia/inducido químicamente , Antiinflamatorios/efectos adversos , Asma/tratamiento farmacológico , Beclometasona/efectos adversos , Prednisolona/efectos adversos , Administración por Inhalación , Administración Oral , Adulto , Antiinflamatorios/administración & dosificación , Antiinflamatorios/uso terapéutico , Beclometasona/administración & dosificación , Beclometasona/uso terapéutico , Quimioterapia Combinada , Femenino , Humanos , Inmunoglobulinas/sangre , Inmunoglobulinas/clasificación , Masculino , Persona de Mediana Edad , Prednisolona/administración & dosificación , Prednisolona/uso terapéutico , Factores de TiempoRESUMEN
BACKGROUND: Leukotrienes (LTs) are important in asthma, and LT modifiers modulate antigen-induced asthma. Overproduction of LT by suppression of cyclooxygenase activity is involved in patients with aspirin-intolerant asthma (AIA). METHODS: House dust mite (HDM) inhalation provocation tests were performed in HDM-sensitive asthmatic inpatients without AIA (HDM group; n = 6), and aspirin oral provocation tests were performed in AIA patients (ASA group; n = 7). Tests were repeated using the same regimen after 7 days of treatment with pranlukast, an LT receptor antagonist (LTRA). The effects of pranlukast on changes in sputum LTC(4)-LTD(4), eosinophil cationic protein (ECP), eosinophil count, urinary LTE(4)/creatinine, 11-dehydrothromboxane B(2) (11-dhTXB(2))/creatinine, serum LTC(4)-LTD(4), ECP, and peripheral blood eosinophil count, during immediate asthmatic reaction (IAR) and late asthmatic reaction (LAR) in the HDM group and during IAR in the ASA group for each test, were compared in each group. RESULTS: In the HDM group, IAR and LAR were observed. Sputum LTC(4)-LTD(4) and urinary LTE(4)/creatinine increased significantly both during IAR and LAR. Sputum ECP increased during IAR and further increased during LAR. Eosinophil count in the sputum did not increase during IAR but significantly increased during LAR. Pranlukast suppressed the fall in FEV(1) both during IAR and LAR (73.8% and 51.9%, respectively) and inhibited the increase in sputum eosinophil count during LAR and sputum ECP during IAR and LAR. In the ASA group, aspirin-induced IAR was associated with a fall in urinary 11-dhTXB(2)/creatinine, increased the levels of sputum LTC(4)-LTD(4) and ECP and urinary LTE(4)/creatinine. Pranlukast suppressed IAR and inhibited the increase of the level of sputum ECP, but failed to change aspirin-induced LT production in the sputum and urine. The levels of sputum LTC(4)-LTD(4) and urinary LTE(4)/creatinine in the stable phase in the ASA group were significantly greater than those in the HDM group. CONCLUSION: Our results indicated that HDM-provoked asthma is associated with overproduction of LT with an antigen-antibody reaction, while AIA is associated with overproduction of LT with a shift to the 5-lipoxygenase series of the arachidonate cascade. LTRA may be useful against both types of asthma through inhibition of LT activity and eosinophilic inflammation of the airways.